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Abstract #27986 Published in IGR 13-1
Interaction of the antiglaucoma prostanoid latanoprost with the prostaglandin transporter OATP2A1
Kraft ME; Zolk O; Welge-Lussen U; Schlotzer-Schrehardt U; Kruse FE; Glaeser H; Mandery K; Konig J; Fromm MFBritish Journal of Clinical Pharmacology 2009; 68: 3
Introduction Mechanisms of ocular uptake and distribution of prostanoids for glaucoma treatment are not well understood. We hypothesized that OATPs are responsible for uptake of clinically used prostanoids (e.g. latanoprost) into ocular tissues and might contribute to interindividual differences in drug concentrations and effects. Methods and Materials To investigate whether transporters are involved in the intraocular disposition of antiglaucoma prostanoids, mRNA levels of prostaglandin uptake (OATP2A1 and OATP2B1) were determined in human ocular tissues (choroidea, retina, iris, ciliary body, lens, cornea, n = 5) by quantitative real-time RT-PCR. Expression of OATP2A1 and OATP2B1 protein was studied by immmunofluorescene on cryosections of the anterior and posterior eye segment. Stably transfected HEK cells overexpressing either OATP2A1 or OATP2B1 were used to test the inhibitory interactions of latanoprost and its active metabolite latanoprost acid with the uptake of prototypical substrates (bromosulfophthalein [BSP] and prostaglandin E2 [PGE2]) and whether latanoprost and its acidic metabolite are substrates of these OATPs. Results Both OATP2A1 and OATP2B1 mRNA were expressed in ocular tissues with highest levels in the choroidea. Localization of OATP2A1 protein was detected primarily in corneal endothelium, iris vessels and ciliary epithelium facing the aqueous humor. In contrast, OATP2B1 showed strong immunofluorescence in choroid vessels. Both latanoprost and its active acidic metabolite were potent inhibitors of OATP2A1 mediated PGE2 uptake (IC50 latanoprost 0.7 (mu)M; IC50 acid 3.2 (mu)M) as well as of OATP2B1 mediated BSP uptake (IC50 latanoprost 23 (mu)M; IC50 acid 88 (mu)M). The active metabolite of latanoprost, latanoprost acid, was a high affinity substrate of OATP2A1 (Km 6.3 (mu)M, Vmax 83.5 pmol/mg protein/min), but a low affinity substrate of OATP2B1 (Km 103 (mu)M, Vmax 213.9 pmol/mg/min). In contrast, both OATPs did not transport the ester prodrug latanoprost. Conclusion Given the in vitro functional characteristics of OATP2A1 and OATP2B1 uptake transporters and their expression pattern in the human eye, the present results support a role of these transporters in the intraocular disposition of therapeutically used prostanoids, such as latanoprost. In particular, OATP2A1 might be responsible for the clearance of latanoprost from aqueous humor.
M.E. Kraft. Institute of Experimental and Clinical Pharmacology, Toxicology Friedrich-Alexander-University Erlangen-Nuremberg, Fahrstrasse 17, Erlangen, Germany.
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
3.8 Pharmacology (Part of: 3 Laboratory methods)
3.6 Cellular biology (Part of: 3 Laboratory methods)
